Effect of Long-Term Administration of α-Lipoic Acid on Retinal Capillary Cell Death and the Development of Retinopathy in Diabetic Rats

Abstract

Oxidative stress is increased in the retina in diabetes, and it is considered to play an important role in the development of retinopathy. ␣-Lipoic acid, a thiol antioxidant, has been shown to have beneficial effects on polyneuropathy and on the parameters of oxidative stress in various tissues, including nerve, kidney, and retina. The purpose of this study was to examine the effect of ␣-lipoic acid on retinal capillary cell apoptosis and the development of pathology in diabetes. Retina was used from streptozotocin-induced diabetic rats receiving diets supplemented with or without ␣-lipoic acid (400 mg/kg) for 11 months of diabetes. Capillary cell apoptosis (by terminal transferase-mediated dUTP nick-end labeling) and formation of acellular capillaries were investigated in the trypsin-digested retinal microvessels. The effect of ␣-lipoic acid administration on retinal 8-hydroxy-2deoxyguanosine (8-OHdG) and nitrotyrosine levels was determined by enzyme-linked immunosorbent assay. ␣-Lipoic acid administration for the entire duration of diabetes inhibited capillary cell apoptosis and the number of acellular capillaries in the retina, despite similar severity of hyperglycemia in the two diabetic groups (with and without ␣-lipoic acid). Retinal 8-OHdG and nitrotyrosine levels were increased by over twofold and 70%, respectively, in diabetes, and ␣-lipoic acid administration inhibited these increases. Our results demonstrate that the long-term administration of ␣-lipoic acid has beneficial effects on the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine in the retina. ␣-Lipoic acid supplementation represents an achievable adjunct therapy to help prevent vision loss in diabetic patients. Diabetes 53

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

“…The role of ROS in 'memory' of high glucose stress in diabetic retina The next experiment was to determine whether the persistence of hyperglycaemic stress could be interrupted in the rat diabetic model in vivo, using the mitochondrial antioxidant nutritional supplement, ALA, which has previously been shown to interrupt target organ damage when given chronically to diabetic animals [20]. The addition of ALA to the last week of normalised glucose resulted in significant decreases in most of the hyperglycaemic stress markers in the retina of diabetic animals (Fig.…”

“…Blood glucose levels were in the following ranges: 5.8-8.0 mmol/l in non-diabetic rats, 17-22.8 mmol/l in diabetic rats and 4.8-5.6 mmol/l in the last week of treatment in insulin-treated animals. ALA (racemic mixture; Sigma Chemical) was prepared in 0.9% sodium chloride, pH 7.4, snap-frozen, stored at −80°C and aliquots thawed daily just before injection [20]. Animals receiving ALA were injected intraperitoneally with 75 mg/kg ALA each day, while all other animals received daily injections of 0.9% sodium chloride, pH 7.4.…”

Effect of R-(+)-α-lipoic acid on experimental diabetic retinopathy

“…While this paper was being prepared, Kowluru and Odenbach published data on the racemic mixture of α-lipoic acid [37]. They showed that the oral administration of 400 mg/kg body weight over 11 months in Wistar rats reduced retinal oxidative stress and the formation of acellular capillaries.…”

Vascular endothelial growth factor in eye disease

“…10) (El-Remessy, 2003a;Graier et al, 1999;Graier et al, 1997;Graier et al, 1996) resulting in peroxynitrite formation. Research demonstrating increased levels of the peroxynitrite biomarker nitrotyrosine in retinas of diabetic patients and experimental animal models supports this concept and implies a role for peroxynitrite in the development of diabetic complications (Abu El-Asrar et al, 2004;Du et al, 2002;ElRemessy, 2003b;Kowluru and Odenbach, 2004;Obrosova et al, 2005). Studies in animal and tissue culture models have demonstrated that increased peroxynitrite formation is directly correlated with diabetes, high glucose-induced VEGF expression, and increased retinal vascular permeability (El-Remessy, 2003a;El-Remessy, 2003b;El-Remessy et al, 2006;El-Remessy et al, 2005).…”